A nociceptor, by definition, identifies one of the nonadapting free nerve endings typically found in the skin and in the deeper tissues such as the arterial walls, periosteum, and surfaces of joints which responds to one or more types of noxious or damaging stimuli. Such stimuli include extreme temperature and mechanical trauma which are mediated by various chemical agents. Signals from these receptors are perceived primarily within the spinal cord of the Central Nervous System ("CNS") as pain; and the duration of effect is perceived as acute or chronic pain. A nociceptive response is thus mediated by a sensory receptor that responds to noxious and damaging stimuli, which are perceived as painful sensations; it is also a term used to describe a reflex or response to such a noxious stimulus.
Accordingly, nociception or pain is a protective mechanism that occurs when living tissues are threatened or are in the process of being damaged which causes the living individual to react to remove the painful stimulus.
Many research investigations have been reported and much scientific literature exists regarding pain receptors, contributions of the autonomic nervous system to painful stimulation, the transmission of pain signals, the physiological and chemical reactions to pain, and therapeutic methods for treating pain. Representative examples of the extensive literature on the subject are the following: Textbook Of Pain, (Wall and Melzack, editors), 2nd Edition 1989; Management Of Pain, (Bonica, J. J., editor), Lea and Febiger, 1953; Clinical Pharmacokinetics Of Analgesic Drugs (Prithri, R. P., editor), Yearbook Medical Publishers, 1986; A Synopsis Of Anesthesia, 10th edition, 1987; Pain, Discomfort and Humanitarian Care, (Bonica, J. J., editor), Elsevier Publishing, 1980; Essentials Of Medicine, W. B. Saunders Company, 1986; Correlative Neuroanatomy and Functional Neurology, (Joseph G. Chusid, editor), Lange Medical Publications, 1985; Pharmacology and Physiology in Anaesthetic Practice, (Robert K. Stoelting, editor), J. B. Lippincott Company, 1991.
From this literature and numerous reported research investigations, a conceptual model of pain transmission has been developed and generally accepted which includes ascending excitatory afferent pain pathways, cortical integration, descending inhibitory pain pathways, and an extensive neurochemistry that includes a variety of different neuromodulators and neurotransmitters Cousins, N. J. and L. E. Mather, Anesthesiology 61:276-310 (1984)!. Basically, nociceptive impulses traveling via afferent nerves from pain receptors enter the dorsal horn of the spinal cord. Then, at this site, i.e., the 1st spinal synapse, a release of excitatory neurotransmitters (such as an 11-amino acid peptide known as substance P) occurs which is necessary for rostral transmission of pain impulses Yaksh, T. L. and D. L. Hammond, Pain 13:1-86 (1982)!. Functionally, it has been noted and demonstrated that the release of substance P into the cerebral spinal fluid is inhibited by prior or concurrent administration of intrathecal morphine Yaksh, et al., Nature 286:155-156 (1980)!. In addition, a depletion of substance P renders animals insensitive to noxious thermal stimuli. Although the generally accepted model of pain transmission includes a complex system of multiple pathways and chemical agents, substance P and opioid alkaloids such as morphine are two prototypic examples of chemical compounds and agents which are commonly recognized by research investigators, clinicians, and other practitioners in this art as having directly antagonistic and completely opposite roles and functions in the mediation of spinal nociceptive processes.
Thus, it is useful here to summarily review the generally recognized chemical characteristics, pharmacological attributes, and functional roles and interactions of opioid alkoids of which morphine sulfate is the prototypic example; and in addition, to review its pharmacological relationship and functional interaction with the tachykinin, substance P (or "SP") in the elicitation and the modulation of a nociceptive response in a living subject. A excellent general review is presented by The Pharmacological Basis of Therapeutics Gilman et al, editors, MacMillan Publishing Company, seventh edition, 1985, Chapter 22, pages 491-531!, the text of which is expressly incorporated by reference herein.
Opioids and opioid agonists designate a group of pharmacologically active compounds that are, in varying degrees, opium-or morphine-like or are related in their structure and/or properties. Opioids are employed primarily as analgesics; interact with several closely related types of receptors; and share some properties in common with the endogenous or three naturally occurring families of opioid peptides--i.e., the enkephalins, the endorphins, and the dynorphins. Historically, the physiological effects of opium--the parent of all opioids--have been known for many millennia. Opium is derived from the juice of the poppy; and it was first introduced mainly for the control of dysenteries. The analgesic and anesthetic effects of opium were well recognized by the 16th century, as were the toxic and addictive dangers of opium for the user. Opium contains more than 20 distinct alkaloids, the first of which, morphine, was isolated in 1806. Codeine and papaverine were then recovered in 1832 and 1848 respectively. By the middle of the nineteenth century, the use of partially-pure alkaloids rather than crude opium preparations became the prevalent practice.
Morphine and the morphine-related opioids produce their major effects on the central nervous system ("CNS") and the enteric nervous system. The physiological effects are remarkably diverse and include: analgesia, drowsiness, changes in mood, respiratory depression, decreased gastrointestinal motility, nausea, vomiting, and alterations in endocrine and autonomic function. Furthermore, when morphine or other opioid analgesics are administered for the relief of pain and to provide an antinociceptive effect at the spinal level, the physician must recognize that only symptomatic treatment is being provided and the underlying pathology remains. The physician must therefore constantly weigh the benefits of this immediate relief against its costs and risks to the patient. A major associated risk is that repeated daily administrations of morphine or morphine-like opioids will eventually produce significant tolerance to the therapeutic effects of the drug as well as initiating some degree of physical dependence. The degree of tolerance and physical dependence will vary with the particular opioid employed, the frequency of administration, and the quantity of opioid administered. In addition, the development of psychological dependency is always a major factor. Accordingly, any decision to relieve the symptomology of chronic pain via administration of an opioid may be short sighted and can be an actual disservice to the patient. Furthermore, the physician is constantly cautioned to employ measures other than opioid drugs to relieve chronic or acute pain when such alternative methods are effective and available. Such alternative measures typically include the use of local nerve block, antidepressant drugs, electrical stimulation, acupuncture, hypnosis, or behavioral modification Reuler et al., Ann. Intern. Med. 93:588-596 (1980)!.
When given therapeutically, morphine and most opioids are typically administered intravenously or parenterally in milligram (mg) doses and provide a duration of action ranging typically between 1-5 hours. Table A below provides a representative listing of opioid analgesics with respect to dosage and duration of action.
TABLE A ______________________________________ A Comparison of Opioid Analgesics DURATION NONPROPRIETARY TRADE DOSE* OF ACTION* NAME NAME (mg) (hours) ______________________________________ Morphine 10 4-5 Heroin 4 (2-8) 3-4 (diacetylmorphine) Hydromorphone Dilaudid 1.5 4-5 (dihydromorphinone) Oxymorphone Numorphan 1.0-1.5 4-5 (dihydrohydroxy- morphinone) Metropon 3.5 4-5 (methyldihydro- morphinone) Codeine 120 (10-20) (4-6) Hyrocodone Hycodan (5-10) (4-8) (dihydrocodeinone) Drocode SYNALGOS-DC 60 4-5 (dihydrocodeine) Oxycodone 10-15 4-5 (dihydrohydroxy- codeinone) Pholcodine (5-15) (4-5) (.beta.-morpholinylethyl- morphine) Levorphanol Levo-Dromoran 2 4-5 Methadone Dolophine 8-10 3-5 Dextromoramide Palfium 5-7.5 4-5 Dipipanone 20-25 4-5 Phenadoxone 10-20 1-3 Meperidine DemeroL 75-100 2-4 Alphaaprodine Nisentil 40 1-2 ______________________________________ *Dose shown is the amount given subcutaneously that produces approximatel the same analgesic effects as 10 mg of morphine administered subcutaneously. The figures in parentheses are the doses and the duration of action for oral, antitussive doses: they are not necessarily equieffective doses. Duration of action shown is for analgesic effects after subcutaneous administration: after intraveneous administration, pea effects are somewhat more pronounced but overall effects are of shorter duration. The doses and durations shown in this table are reproduced from The Pharmacological Basis of Therapeutics, (Gilmon et al., editors), 7th Edition, MacMillan Publishing Co., 1985, p. 505, and are based primarily on Eddy, et al., Bull, WHO 46:639-719 (1969); Reynolds, A.K. and L.O. Randall, Morphine and Allied Drugs, University of Toronto Press, Toronto, 1957; and Lsagna, L., Pharmacol. Rev. 16:47-83 (1964).
An extensive pharmacological literature has documented the analgesic properties of morphine and morphine related opioid agonists when administered directly at the spinal level Kitahata, L. N. and J. G. Collins, Anesthesiology 54:153-163 (1981); Yaksh T. L., Pain 11:293-346 (1981); Cousins, M. J. and L. E. Mather, Anesthesiology 61:276-310 (1984)!. Opioid-induced analgesia is mediated by neural networks at several areas within the central nervous system and involves several distinct but interrelated neurotransmitter systems. Although opioids do not alter the threshold or responsivity of afferent nerve endings to noxious stimulation or impair the conduction of the nerve impulse along peripheral nerves, they do decrease conduction and transmission of impulses of primary afferent fibers after entering the spinal cord. In general, opioids depress electrical activity at the spinal level. There are 3 major types of opioid receptors (.mu., .kappa., .delta.) on the terminal axons of primary afferents within laminae 1 and 2 of the spinal cord and within the spinal nucleus of the trigeminal nerve. Morphine and morphine-related drugs acting at these sites decrease the release of neurotransmitters, such as substance P, that normally mediate the transmission of pain impulses. Thus, at the spinal level, opioid analgesics directly counteract, contradict, and neutralize the pharmacological activity of substance P as well as other neurotransmitters in-vivo. Neutralization can also be expressed as physiological antagonism; neutralization or physiological antagonism is a major mechanism by which pain relief may be obtained.
In addition, to direct analgesic effects, morphine-like drugs also relieve suffering by altering the emotional component of the painful experience. As a consequence, if little or no emotional support is provided externally--i.e., by biofeedback mechanisms, some patients may require considerably more than the average dose of an opioid to experience any relief from pain; similarly, others may require more frequent administration. Therefore, out of an exaggerated concern for eliminating the possibility of inducing addiction, many physicians frequently tend to prescribe initial doses of opioids that are either too low, or too infrequent a time interval to successfully alleviate pain. Consequently, they respond to the patient's continued complaints of pain with an even more exaggerated concern about dependency. This is done despite the high probability that the request for more opioid is only the expected consequence of the inadequate dosage originally prescribed Sriwatanakul et al., J.A.M.A. 250:926-929 (1983)!. In this regard, it has also been documented that children are probably more apt to receive inadequate dosages for pain than are adults based on the same type of reasoning concerning tolerance and dependence Schechter, N. L., Curr. Probl. Pediatr. 15 (1985)!. Finally, it is useful to remember that the typical initial dose of morphine (10 mg/70 kg body weight) relieves post-operative pain satisfactorily in only about two-thirds of patients See page 511, Gilman et al., The Pharmacological Basis of Therapeutics!.
In contrast to the pharmacology of opioids, the undecapeptide substance P ("SP") has long been recognized and identified as a neurotransmitter intimately associated with the transfer of painful or nociceptive stimuli from peripheral receptive fields into the central nervous system Jessell, T., Handbook Psychopharmacol. 16:1-105 (1983); Pernow, B., Pharmacol. Rev. 35:85-141 (1983); Helke, et al., FASEB J. 4:1606-1615 (1990)!. Substance P is the prototypic member of a family of related peptides named tachykinins, all of which were initially characterized by contractile activity on isolated smooth muscle preparations. After its original discovery by Von Euler and Gaddum J. Physiol. 72:74 (1931)!, substance P was found to be present in the brain, spinal cord, spinal ganglia, and intestine of all vertebrates including man. While its various biological activities have long been recognized, the actual amino acid sequence structure and solid-phase synthesis of the peptide was accomplished only in 1971 Chang et al., Nature New Biol. 232:86 (1971)!.
Since the specific identification and synthesis of substance P was made and the ensuing availability of the peptide for research investigations occurred, it has been accepted that substance P regulates nociceptive information at the first synapse in the spinal cord--on the basis that it is found in small-diameter sensory fibers which mediate nociceptive inputs, and on the basis that it specifically excites nociceptive neurons in this spinal region Henry, J. L., Brain Res. 114:439-451 (1976); Hokfelt et al., Brain Res. 100:235-252 (1975); Torebjork, H. E., Acta Physiol. Scand. 92:374-390 (1974)!. This consensus view has been substantiated by considerable evidence; high concentration nerve terminals containing substance P are in opposition to specific receptors for substance P in regions of the dorsal horn where nociception is initially integrated Hokfelt et al., Proc. Natl. Acad. Sci. U.S.A. 74:3081-3085 (1977); Cuello et al., J. Neurochem., 29:747-751 (1977); Quirion et al., Nature (London) 303:714-71 (1983); Ruda et al. Prog. Brain Res. 66:219-268 (1986)!; substance P is released in the spinal cord in-vivo specifically upon activation of nociceptive primary sensory fibers Theriault et al, Brain Res. 170:202-213 (1979); Brodin et al., Neurosci. Lett. 76:357-362 (1987); Go, D. L. W. and T. L. Yaksh, J. Physiol. (London) 391:141-167 (1987); Duggan et al., Brain Res. 451:261-273 (1988); Cridland, R. A. and J. L. Henry, Brian Res. 462:15-21 (1988)!; and the release of substance P is blocked by administration of morphine and opioid peptides in-vivo and in-vitro Go, V. O. W. and Yaksh, T. L., J. Physiol. (London) 391:141-167 (1987); Jessell, T. N. and L. L. Iversen, Nature (London) 268:549-551 (1977); Yaksh et al., Nature (London) 286:155-157 (1980)!.
Furthermore, it has been recognized that direct application of large microgram doses of substance P into the lumbar spinal subarachnoid produces hyperalgesia--i.e., an increased sensitivity to pain Yasphal et al., Pain 14:155-167 (1982); Sawynok et al., Neuropharmacology 23:741-747 (1984); Cridland, R. A. and J. L. Henry, Brain Res. 381:93-99 (1986)!; and that intrathecal administration of morphine blocks the hyperalgesic effects of intentionally administered substance P Hylden J. L. K. and G. L. Wilcox, Eur. J. Pharmacol., 86:95-98 (1983); and J. Pharmacol. Exp. Ther. 226:398-404 (1983)!. Based on such overwhelming evidence, substance P has long been identified and accepted as a neuromodulator intimately associated with the transfer of painful or nociceptive stimuli De Koninck, Y. and J. L. Henry, Proc. Natl. Acad. Sci. USA 88:11344-11348 (1991); Wiesenfeld-Hallin et al., Brain Res. 551:157-162 (1991); Chang et al., Anesthesiology 70:672-677 (1989); Nance, P. W. and J. Sawynok, J. Pharmacol. Exp. Ther. 240:972-977 (1987); Frenk et al., Brain Res. 455:223-231 (1988); Moochhala, S. N. and J. Sawynok, Br. J. Pharmacol. 82:381-388 (1984); Marchand et al., J. Biol. Chem. 265:264-273 (1990); Shimonaka et al., J. Neurochem. 59:81-92 (1992); Kream et al., Proc. Natl. Acad. Sci. USA 82:4832-4836 (1985)!.
One oddity regarding substance P, however, has been observed and reported. In contrast to the direct spinal effects of substance P, administration of small nanogram doses of this peptide at supraspinal or brainstem sites has been shown to evoke a modest analgesic response Stewart et al., Nature 262:784-785 (1976); Fredrickson et al., Science 199:1359-1362 (1978); Malick, J. and J. Goldstein, Life Sci. 23:835-844 (1978)!. This evoked effect is presumably caused by a substance P-induced excitation of descending modulatory systems; and has been operationally characterized as opioid-like in nature by virtue of its reversibility by the opioid antagonist naloxone Naranjo et al., Peptides 7:419-423 (1986)!. Thus, a few research investigators have proposed that supraspinal or brainstem administration of substance P secondarily causes the release of endogenous opioid peptides both in the brain stem and the spinal cord, thereby producing an opioid-dependant analgesia. This proposed mechanism is supported by experimental data demonstrating an evoked release of endogenous opioid peptides by substance P Tang et al., Neuropharmacology 22:1147-1150 (1983); Iadarola et al., Eur. J. Pharmacol. 121:39, 48 (1986)!.
Overall therefore, and with particular respect to therapeutic spinal administrations of morphine and morphine-related opioid agonists, it is generally recognized and long been accepted that substance P and the opioid alkaloids are pharmacologically active compounds which have opposite and directly contradictory roles and functions in the mediation of spinal nociceptive processes. One class of compound is generally recognized to contradict and neutralize the pharmacological activity of the other, both in-vivo and in-vitro. Equally important, current good medical practice and therapeutic procedures support and recommend the long established therapeutic regimen of administering morphine or other opioid agonists as one effective means by which to overcome and relieve both acute and chronic pain and to provide analgesia for the patient. The physician, the clinician, and the research investigator working in this field thus have no factual basis for believing or expecting that opioids and substance P may be employed together in combination to any advantage; and, in particular, may be employed together in a manner where substance P markedly potentiates and enhances the antinociceptive effects of morphine when concurrently administered at the spinal level.